Unregulated cell growth is the hallmark of tumors and cancers and other cell proliferative disorders. The cellular processes controlling cell division and cell proliferation are complex, involving an intricate interplay between gene products that promote cell division and growth and those that hold such processes in check. Positive regulators of growth and proliferation are generally described as proto-oncogenes, which are the normal counterparts of altered genes and their gene products known to promote tumor and cancer formation. Proto-oncogenes promote cell division and negatively control cell apoptosis. Uncoupling the activity of these gene products from their normal regulated state converts the proto-oncogenes to oncogenes. Normal function of proto-oncogenes includes growth factors, growth factor receptors, cellular signal transduction molecules, and nuclear factors. Activation of the proto-oncogenes into oncogenic forms can occur in a variety of ways, including gene mutation, amplification, gene translocation, and viral activation.
Tumor suppressors, as opposed to the proto-oncogenes, generally exert a negative effect on cell growth, promote apoptosis of cells, inhibit cell cycle progression, and affect invasive and metastatic potential. In some instances, tumor suppressors can counter the activity of oncogenes even in their altered forms. Upon loss or inhibition of tumor suppressor function, the unregulated activity of proto-oncogenes or their corresponding oncogenic forms leads to cell transformation and carcinogenesis. Gene mutation or deletion, suppressed transcription, increased degradation, or abnormalities of associated proteins that work in concert with the tumor suppressors may compromise tumor suppressor activity. Tumor suppressor genes act as recessive alleles such that a cell with a normal allele along with a mutant allele still behaves normally. Thus, loss of the normal allele, also called loss of heterozygozity (LOH), characterizes some types of abnormal cell growth and proliferation. Genomic instability arising as a consequence of oncogene activity and disruption of normal cell division controls can increase the probability of LOH and thus the occurrence of the transformed phenotype by oncogenes.
Treatment of cell proliferative disorders can target the oncogenes and/or the tumor suppressors affected in the transformed cells. However, a disorder arising from a loss-of-function, such as a tumor suppressor, is typically more problematic when attempting to treat the underlying molecular defect than treating the underlying molecular defect in a disorder arising from a gain-of-function change, such as activation of an oncogene. Altering cellular processes to provide the lost cellular function is not practicable in many cases. Thus, even for cell proliferative disorders arising from loss of tumor suppressor activity, therapy is typically directed at the dysregulated molecules (e.g., proto-oncogenes) that act as a consequence of the lost tumor suppressor function. Although many molecular targets have been identified, such as non-receptor and receptor based protein kinases, the complex nature of the cellular regulatory mechanisms at play in cell proliferation and growth would indicate that other molecules that could be targets of therapy remain to be identified. Some of these will be unknown while others may be known but not linked to cell proliferative disorders.
Thus it is desirable to identify other cellular molecules that act in an oncogenic manner in cell proliferative disorders, either as a consequence of alteration of its own activity or as a result of loss of a cellular function that act to regulate its activity. Upon identification of such molecules, compounds specifically directed to that cellular molecule can be identified and used, either independently or in combination with other known therapies, to treat the cell proliferative disorder.